1. Field of the Invention
The present invention pertains to novel non-N-methyl-D-aspartic acid excitatory amino acid (EAA) antagonists and particularly to novel, potent and selective antagonists of kainic acid (KA) and AMPA-type [(RS)-alpha-aminomethyl-3-hydroxy-5-methylisoxazole propionic acid]-type receptors having anxiolytic, anticonvulsant, antiepileptic, analgesic, antiemetic, neuroprotective and cognition enhancing actions achieved through the antagonisms of these receptors. In particular, the invention is directed to: 2-[(alkyl)phenyl]-2-aminoalkanoic acids and their interaction with KA and AMPA receptors, their pharmaceutically acceptable salts, and to uses thereof.
2. Description of the Prior Art
Excitatory amino acids (EAA) mediate a substantial portion of the chemical synaptic activity occurring in the central nervous system. Current understanding recognizes at least three major ionotropic receptors for EAAs. Most commonly identified by prototypical agonists, these include:
(1) receptors activated by AMPA [(RS)-alpha-aminomethyl-3-hydroxy-5-methylisoxazole propionic acid], a cyclic analog of L-glutamate (GLU), (2) receptors recognizing the pyrrolidine neurotoxin kainic acid (KA), and (3) receptors responding to N-methyl-D-aspartate (NMDA), a synthetic analog of L-aspartate (D. R. Curtis, A. W. Duggar, D. Felix, G. A. R. Johnston, A. K. Tebecis and J. C. Watkins, Brain Res., 41, 283-301 (1972); J. C. Watkins and R. H. Evans., Ann. Rev. Pharmacol. Toxicol., 21, 165-204 (1981); A. C. Foster and G. Fagg, Brain Res. Rev. 7, 103-164 (1984)]. In addition to these major channel-linked receptors, evidence now suggests the presence of "metabotropic" EAA receptors which directly activate second messenger responses (D. Schoepp, J. Bockaert and F. Sladeczek, In C. Lodge and G. L. Collingridge (eds.) Tr. Pharmacol. Sci., Special Report, "The Pharmacology of Excitatory Amino Acids," Elsevier, Cambridge, UK., pages 74-81, (1991)]. Furthermore, it is now apparent that the NMDA-mediated ionotropic responses are subject to complex regulatory influences and, that this particular recognition site may exist as a supramolecular entity similar to the GABA/benxodiazepine/barbiturate effector proteins [E. Costa, Neuropsychopharmacology, 2, pages 167-174 (1989)]. PA1 5-methyl-2-(3-carboxypropyl)phenylalanine PA1 5-methyl-2-(3-sulfonoethyl)phenylalanine PA1 5-methyl-2-(3-carboxyethyl)phenylalanine PA1 5-methyl-2-(2'-tetrazolylethyl)phenylalanine PA1 3,5-dimethyl-2-(2-carboxypropyl)phenylalanine PA1 3,5-dimethyl-2-(2-sulfonoethyl)phenylalanine PA1 3,5-dimethyl-2-(2-carboxyethyl)phenylalanine PA1 3,5-dimethyl-2-(2'-tetrazolylethyl)phenylalanine PA1 5-chloro-2-(2-carboxypropyl)phenylalanine PA1 5-chloro-2-(2-sulfonoethyl)phenylalanine PA1 5-chloro-2-(2-carboxyethyl)phenylalanine PA1 5-chloro-2-(2'-tetrazolylethyl)phenylalanine PA1 5-methyl-(2-carboxypropyl)phenylalanine PA1 5-methyl-(2-sulfonoethyl)phenylalanine PA1 5-methyl-(2-carboxyethyl)phenylalanine PA1 5-methyl-(2'-tetrazolylethyl)phenylalanine PA1 5-fluoro-2-(2-carboxypropyl)phenylalanine PA1 5-fluoro-2-(2-sulfonoethyl)phenylalanine PA1 5-fluoro-2-(2-carboxyethyl)phenylalanine PA1 5-fluoro-2-(2'-tetrazolylethyl)phenylalanine PA1 4,5-dichloro-2-(2-carboxypropyl)phenylalanine PA1 4,5-dichloro-2-(2-sulfonoethyl)phenylalanine PA1 4,5-dichloro-2-(2-carboxyethyl)phenylalanine PA1 4,5-dichloro-2-(2'-tetrazolylethyl)phenylalanine
In general, EAA agonists are potent convulsants in animal models. Additionally, AMPA, KA and the endogenous NMDA agonist, quinolinic acid (QUIN) and the mixed ionotropic/metabotropic agonist ibotenic acid have been used to produce laboratory models of neurodegenerative disorders [K. Biziere, J. T. Slevin, R. Zaczek, J. S. Collins and J. T. Coyle. IN H. Yoshida, Y. Hagihara and S. Ebashi (eds.), "Advances in Pharmacology and Therapeutics," Pergamon, New York, 1982, pp. 271-276; R. Schwarcz, W. O. Whetsell and R. M. Mango, Science, 219, pages 316-318 (1983)]. It has been suggested for some time that a dysfunction in EAA neurotransmission may contribute to the neuropathology associated with epilepsies and neurodegenerative conditions [B. Meldrum and M. Williams (eds.), "Current and Future Trends in Anticonvulsant, Anxiety and Stroke Therapy," Wiley Liss, New York, (1990)].
The development of selective NMDA antagonists has further expanded the understanding of EAA neurotransmission, physiology and pathophysiology in the mammalian brain. In particular, substantial preclinical evidence is now available suggesting that NMDA receptor antagonists may be useful as anxiolytics, anticonvulsants, antiemetics [European Patent Application No. 432,994], antipsychotics or muscle relaxants, and that these compounds may prevent or reduce neuronal damage in instances of cerebral ischemia, hypoxia, hypoglycemia or trauma [R. P. Simon, J. H. Swan, T. Griffiths and B. S. Meldrum, Science, 226, pages 850-852 (1984); D. N. Stephens, B. S. Meldrum, R. Weidman, C. Schneider and M. Grutzner, Psychopharmacology, 90, pages 166-169 (1986); D. Lodge and G. L. Collingridge (eds.) "The Pharmacology of Excitatory Amino Acids," Elsevier Trends Journals, Cambridge, UK. (1991); A. I. Fader, J. A. Ellison and L. J. Noble, Eur. J. Pharmacol., 175, pages 165-174 (1990)].
Given the broad therapeutic potential of EAA antagonists, it is not surprising that efforts have been initiated to identify additional antagonist compounds. The advent of potent and selective antagonists of EAAs exemplified by .alpha.-amino-.omega.-phosphonoalkylcarboxylic acids has provided a point of departure for the pharmacologic intervention of EAA action at their receptors [J. C. Watkins, Can. J. Physiology Pharmacol., 69, 1064-1075 (1991)]. While there has been substantial success in finding competitive and non-competitive antagonists of NMDA receptors, there are few reports of potent and selective antagonists of KA or AMPA-type EAA receptors [J. C. Watkins, P. Krogsgaard-Larsen and T. Honore, In D. Lodge and G. L. Collingridge (eds.), "The Pharmacology of Excitatory Amino Acids," Elseiver Trends Journals, Cambridge, UK., pages 4-12 (1991); M. J. Sheardown, E. O. Nielsen, J. A. Hansen, P. Jacobsen and T. Honore, Science, 247, pages 571-573 (1990); A. Frasden, J. Drejer and A. Shousboe, J. Neurochem., 53, pages 297-300 (1989)]. Identification of such antagonists is important since these agents are expected to share many of the potential therapeutic actions of antagonists of NMDA-type EAA receptors.
In the past, 2-amino-4-(2-phosphonomethylphenyl)butyric acid has been reported by Matoba et al. [Chem. Pharm. Bull. 32, pages 3918-3925 (1984)]. More particularly, Matoba et al. prepared several amino-phosphonic acids and notably, 2-amino-5-phosphonopentanoic acid, 2-amino-4-(2-amino-5-phosphonomethyl-phenyl)butyric acid, 2-(2-amino-2-carboxy) ethylphenyl-phosphonic acid and N-benzylproline-4-phosphonic acid. One of the target compounds, 2-amino-4-(2-phosphonomethylphenyl)butyric acid was synthesized starting with (2-bromoethyl) phenethylbromide. This dibromide was treated with triethyl phosphite to give diethyl (2-(2-bromoethylphenyl)methylphosphonate, and this bromophosphonate derivative was treated with sodium diethyl acetamindomalonate to give the expected acetamidomalonylphosphonate derivative which was purified through a silica gel column. It should be pointed out that none of the Matobe et al. compounds contain substituents on the benzene ring.
Related compounds having NMDA antagonist activity has been reported in Rzeszotarski et al., U.S. Pat. No. 4,657,899. In particular, Rzeszotarski et al. disclose potent and selective EAA neurotransmitter receptor antagonists having the general formula: ##STR2## wherein R.sub.1 and R.sub.2 are the same or different and are selected from the group consisting of hydrogen, lower alkyl, halogen, amino, nitro, trifluoromethyl or cyano, or taken together are --CH.dbd.CH--CH.dbd.CH--; n and m=0, 1, 2, or 3; and the pharmaceutically acceptable salts and the 2-acetamido-2-carboethoxy esters thereof. Rzeszotarski et al. also disclose specific compounds, including 2-amino-3-[2-(2-phosphonoethyl)phenyl]propanoic acid, 2-amino-3-[2-(3-phosphonopropyl)phenyl]propanoic acid, 2-amino-5-[2-phosphonomethylphenyl]pentanoic acid, and 2-amino-3-[2-phosphonomethylphenyl]propanoic acid which are disclosed as antagonists of NMDA and show very low binding affinity for kainate receptors; see Table I on column 13 of U.S. Pat. No. 4,657,899. The valuable pharmacological properties of the present new compounds are particularly surprising in view of the compounds disclosed and described in U.S. Pat. No. 4,657,899.